Recurrent ischemic priapism is an erection disorder of non-willful, excessive penile erection, which afflicts approximately 40% of male individuals with sickle cell disease. The disorder is not trivial, and its consequences include erectile tissue damage, erectile dysfunction, and psychological distress. Currently, satisfactory medical interventions to address the disorder are lacking, in large part because a rational basis for its treatment remains obscure. We have recently elucidated a pathophysiologic mechanism, which involves impairment in the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signaling (erection mediatory) pathway, causing downregulation of phosphodiesterase type 5 (PDEs) function in the penis. PDEs, which serves a regulatory role in NO signaling as a cGMP-specific degradative phosphodiesterase, is therefore insufficiently active in controlling corporal smooth muscle relaxation, resulting in priapism. We have also shown that chronic PDEs inhibitor administration causes PDEs expressional upregulation in penile tissues. These preclinical observations have supported a proposal to use continuous, long-term PDEs inhibitor therapy as an intervention for recurrent priapism in humans. We hypothesize that the therapy reverses downregulated PDEs functional levels in the penis toward normative ranges, thereby protecting against episodes of the disorder. To test this hypothesis, we propose a translational project, which includes both preclinical investigation of the mechanism of action of this treatment and clinical assessment of its utility for treating sickle cell disease-associated priapism. The preclinical component will consist of molecular and physiologic erection experiments following treatment with the prototypical PDEs inhibitor sildenafil in an experimental mouse model of sickle cell disease. The clinical component will be a singlecenter, randomized, double-blind, placebo-controlled study, in which sildenafil will be administered continuously to patients with sickle cell disease and priapism. By way of this translational approach, this project may provide a critical step in introducing an effective, secondary prevention program for patients with sickle cell disease-associated priapism, supported by a rational basis for its use. The project may lead to a major advance in the preservation of the sexual health and psychological well-being of individuals with sickle cell disease afflicted by priapism.